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Drug Interactions between atazanavir and clomipramine

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

clomiPRAMINE atazanavir

Applies to: clomipramine and atazanavir

MONITOR: Product labeling for certain protease inhibitors (PIs) such as amprenavir and atazanavir states that serious and/or life-threatening drug interactions may occur with tricyclic antidepressants (TCAs), presumably due to PI inhibition of TCA metabolism via CYP450 3A4. High plasma levels of TCAs could conceivably lead to serious adverse reactions including QT interval prolongation and ventricular arrhythmias such as ventricular tachycardia and torsade de pointes. However, the clinical significance of such an interaction is unknown, as it has not been studied and there are no case reports of it published in the medical literature. Moreover, many TCAs are thought to be substrates of multiple CYP450 isoenzymes, thus the effects of CYP450 3A4 inhibition alone are unknown. Some TCAs such as desipramine, doxepin, and nortriptyline are also thought to be primarily metabolized by CYP450 2D6, which is not known to be inhibited by most PIs (except ritonavir) to any significant extent.

MANAGEMENT: Until further information is available, caution is advised if protease inhibitors must be used with certain TCAs. Pharmacologic response and plasma TCA levels should be monitored more closely whenever a PI is added to or withdrawn from therapy, and the TCA dosage adjusted as necessary.

References (17)
  1. von Moltke LL, Greenblatt DJ, Cotreau-Bibbo MM, Duan SX, Harmatz JS, Shader RI (1994) "Inhibition of desipramine hydroxylation in vitro by serotonin-reuptake-inhibitor antidepressants, and by quinidine and ketoconazole: a model system to predict drug interactions in vivo." J Pharmacol Exp Ther, 268, p. 1278-83
  2. Vonmoltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI (1995) "Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants." J Clin Psychopharmacol, 15, p. 125-31
  3. Nielsen KK, Flinois JP, Beaune P, Brosen K (1996) "The biotransformation of clomipramine in vitro, identification of the cytochrome p450s responsible for the separate metabolic pathways." J Pharmacol Exp Ther, 277, p. 1659-64
  4. Ghahramani P, Ellis SW, Lennard MS, Ramsay LE, Tucker GT (1997) "Cytochromes p450 mediating the n-demethylation of amitriptyline." Br J Clin Pharmacol, 43, p. 137-44
  5. (2001) "Product Information. Agenerase (amprenavir)." Glaxo Wellcome
  6. Venkatakrishnan K, Schmider J, Harmatz JS, et al. (2001) "Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies." J Clin Pharmacol, 41, p. 1043-54
  7. Shimoda K, Someya T, Yokono A, et al. (2002) "The Impact of CYP2C19 and CYP2D6 Genotypes on Metabolism of Amitriptyline in Japanese Psychiatric Patients." J Clin Psychopharmacol, 22, p. 371-378
  8. Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, Gelbon HV (1999) "Eight inhibitory monoclonal antibodies define the role of individual P-450S in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism." Drug Metab Dispos, 27, p. 102-9
  9. Tacke U, Leinonen E, Lillsunde P, et al. (1992) "Debrisoquine hydroxylation phenotypes of patients with high versus low to normal serum antidepressant concentrations." J Clin Psychopharmacol, 12, p. 262-7
  10. Eap CB, Bender S, Gastpar M, et al. (2000) "Steady state plasma levels of the enantiomers of trimipramine and its metabolites in CYP2D6-, CYP2C19- and CYP3A4/5-phenotyped patients." Ther Drug Monit, 22, p. 209-14
  11. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb
  12. Kirchheiner J, Muller G, Meineke I, Wernecke KD, Roots I, Brockmoller J (2003) "Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics." J Clin Psychopharmacol, 23, p. 459-66
  13. (2003) "Product Information. Lexiva (fosamprenavir)." GlaxoSmithKline
  14. Hartter S, Tybring G, Friedberg T, Weigmann H, Hiemke C (2002) "The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19." Pharm Res, 19, p. 1034-7
  15. Kirchheiner J, Meineke I, Muller G, Roots I, Brockmoller J (2002) "Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers." Pharmacogenetics, 12, p. 571-80
  16. Haritos VS, Ghabrial H, Ahokas JT, Ching MS (2000) "Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin." Pharmacogenetics, 10, p. 591-603
  17. Venkatakrishnan K, Greenblatt DJ, von Moltke LL, Schmider J, Harmatz JS, Shader RI (1998) "Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4." J Clin Pharmacol, 38, p. 112-21

Drug and food interactions

Moderate

clomiPRAMINE food

Applies to: clomipramine

MONITOR: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine. Clomipramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine. The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes. This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

References (4)
  1. Oesterheld J, Kallepalli BR (1997) "Grapefruit juice and clomipramine: shifting metabolitic ratios." J Clin Psychopharmacol, 17, p. 62-3
  2. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Cerner Multum, Inc. "Australian Product Information."
Moderate

atazanavir food

Applies to: atazanavir

ADJUST DOSING INTERVAL: Administration of atazanavir with food enhances oral bioavailability and reduces pharmacokinetic variability. According to the manufacturer, administration with a light meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of a single 400 mg dose of atazanavir by 57% and 70%, respectively, relative to the fasting state. Administration with a high-fat meal resulted in a mean increase of 35% in atazanavir AUC and no change in Cmax compared to fasting. The coefficient of variation of AUC and Cmax decreased by approximately one-half when given with either a light or high-fat meal compared to the fasting state.

MANAGEMENT: To ensure maximal oral absorption, atazanavir should be administered with or immediately after a meal.

References (1)
  1. (2003) "Product Information. Reyataz (atazanavir)." Bristol-Myers Squibb
Moderate

clomiPRAMINE food

Applies to: clomipramine

GENERALLY AVOID: The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills. Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

MANAGEMENT: Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants. Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.

References (3)
  1. Seppala T, Linnoila M, Elonen E, Mattila MJ, Makl M (1975) "Effect of tricyclic antidepressants and alcohol on psychomotor skills related to driving." Clin Pharmacol Ther, 17, p. 515-22
  2. Berlin I, Cournot A, Zimmer R, et al. (1990) "Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects." Psychopharmacology (Berl), 100, p. 40-5
  3. Balant-Gorgia AE, Gay M, Gex-Fabry M, Balant LP (1992) "Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients." Ther Drug Monit, 14, p. 119-24

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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